Access to Hepatitis C Clinical Trials

Mark Antell had hepatitis C for decades before he decided to fight the disease. A chronic viral infection, hepatitis C can slowly damage the liver and cause cirrhosis, cancer or death. “I just got proactive,” says Antell, 63, a federal government retiree in Arlington, Virginia. In 2003, he decided to take the plunge and try the drug regimen to clear the virus from his body.

But four or five months into the process, Antell was almost relieved to learn the treatment had failed. That’s because the standard regimen—a combination of interferon and ribavirin taken for 48 weeks—is so grueling. Previously asymptomatic, Antell soon felt like he had aged decades. “I looked ashen; my hair was falling out; and my joints creaked,” says Antell, who has mild to moderate hemophilia A.

For Antell, the treatment’s impact wasn’t just physical. The word Antell uses to describe his emotional state during treatment is “anhedonic,” or unable to feel pleasure. “I was constantly aware that I was a very sick person,” he says. Six years later, Antell has advanced liver disease. He still hopes to show his three young grandchildren a volcano in Costa Rica, where he travels frequently. Antell knows his options are few: a new therapy that’s more effective and less brutal than the current one, or getting listed for a liver transplant.

Antell and others in the bleeding disorders community are working to make the first option a reality. They’re leading a grassroots movement to give people with bleeding disorders, who are typically excluded from clinical trials for hepatitis C, emergency access to the promising new drugs being studied. Now, the US Food and Drug Administration (FDA) has issued draft guidance that encourages the pharmaceutical industry to allow people with advanced hepatitis C and/or HIV co-infection early access to trial medications. The draft guidance also authorizes waiving liver biopsy in clinical tests for those who would be placed at risk from the procedure, such as people with bleeding disorders. “The key word is ‘urgency,’” Antell says. “At least half the people who have taken the same voyage as I haven’t made it as far.” More are declining daily.

Better Hepatitis C Treatment on the Way?

Antell’s experience is typical among those in the bleeding disorders community who have hepatitis C. Prior to 1992, blood products contaminated with the hepatitis C virus infected as many as 80% of those with bleeding disorders. The current gold-standard treatment is successful in fewer than 50% of patients and even less so in those with genotype 1, the most common form of the virus. In addition, patients can experience troubling side effects, including depression, fatigue, flulike symptoms and anemia. Many also have insomnia, irritability, nausea, diarrhea and decreased platelet counts. But promising new treatments are under development, with some already in phase 3 trials, the last step before seeking FDA approval.

Findings released in May 2010 showed that in a phase 3 trial of the drug telaprevir (manufactured by Vertex Pharmaceuticals), when used in combination with existing treatment, 75% of participants, who had chronic infections with hepatitis C genotype 1 and had not undergone previous treatment, cleared the virus. (While patients can clear the virus, the liver damage and existing liver disease remain.) Another phase 3 telaprevir trial showed that approximately two-thirds of all patients could be treated in 24 weeks, half that of the current regimen. Merck’s new drug boceprevir, also in phase 3 trials, is showing promising results, too. While these new drugs result in a cure more often than previous therapies do, patients still experience some of the troubling side effects seen with interferon and ribavirin.

Unfortunately, people with bleeding disorders don’t have access to these experimental drugs, because they’re usually barred from participating in clinical trials. That’s not surprising, says Margaret V. Ragni, MD, MPH, director of the Hemophilia Center of Western Pennsylvania and a professor of medicine at the University of Pittsburgh. For a researcher, she explains, the ideal trial participant is someone who has the disease being studied and no other complicating conditions. “If you have problems not related to the issue at hand, they may add to adverse events and stand in the way of licensure and getting the drug to market,” she says.

Researchers may also be reluctant to include people with bleeding disorders in hepatitis C trials for fear they might have to drop out or reduce their dose of a new drug, slowing publication of the study’s results. The high rate of co-infection with HIV is another concern, says Ragni. People with HIV, she explains, tend to have a lower response rate to antiviral agents for hepatitis C.

A possible solution, one used in early AIDS drug trials, is a so-called “parallel track” study for people with bleeding disorders. “Then you could look at them as a special group in terms of safety issues or other pertinent outcomes and avoid slowing down the study’s main goals: to complete testing and seek approval for the drug,” Ragni says. Pharmaceutical companies may still hesitate, because such studies would add to their costs.

Hepatitis C in Clinical Trials: A Grassroots Movement

Now a movement is under way to persuade the FDA to give people with bleeding disorders access to potentially life-saving investigational drugs.

Last year, the National Hemophilia Foundation’s (NHF’s) Medical and Scientific Advisory Council (MASAC) issued a recommendation stating that the presence of a bleeding disorder or a requirement for a baseline liver biopsy shouldn’t be grounds for excluding people with bleeding disorders from participating in hepatitis C trials.

NHF has urged the secretary of the US Department of Health and Human Services, the FDA, the National Institutes of Health and other federal agencies to allow individuals with bleeding disorders access to trials. The organization has also signed a citizen petition to the FDA. The petition is the brainchild of Antell and Paul Brayshaw, MPH, president of the Hemophilia Federation of America, a national grassroots organization based in Washington, DC, that assists and advocates for the bleeding disorders community. “We wanted to see if we could influence the regulatory process,” says Brayshaw, 36, of Falls Church, Virginia. Brayshaw has severe hemophilia B and hepatitis C.

Citing desperate need, the petition calls on the FDA to hold a public hearing and provide an “expanded access” pathway that would give individuals with bleeding disorders access to promising investigational therapies.

The pharmaceutical industry’s stance is understandable, says Brayshaw, a client services representative at the Factor Support Network pharmacy. He is an activist who hosted President Obama and others at a backyard forum on healthcare policy in September 2010. “[The industry is] nervous about very vulnerable people getting worse or dying on their product, which could undermine the research and development that they’ve been pursuing for the last several years,” he says.

But, Brayshaw says, the situation for some people with hepatitis C is desperate. “Some people might be able to wait it out until some of these products are further along, but there’s a lot of us who just don’t have that kind of time,” he says. His own hepatitis C treatment trial lasted only a week, scuttled by alarming bloodwork that suggested that liver failure was imminent.

FDA Action

The activists’ efforts appear to be paying off. In response to the petition, the FDA held a hearing in April 2010 that brought together representatives from the government, the bleeding disorders community, other patient advocacy groups and industry. Both Antell and Brayshaw testified.

In September 2010, the FDA issued draft guidance that suggests, in part, that companies offer expanded access to individuals or small groups needing investigational new drugs. “We do encourage that to a certain extent, when needed drugs are sufficiently along in the process that these programs don’t interfere with drug development,” explains Jeffrey S. Murray, MD, deputy director of FDA’s Division of Antiviral Products.

The draft guidance also encourages industry to provide access to two or more investigational drugs or allow people to enroll in multiple programs simultaneously to help prevent drug resistance. In addition, the draft guidance suggests that liver biopsy requirements be waived for people with bleeding disorders.

For Brayshaw, this progress is welcome news and an illustration of activism’s power. “I didn’t plan to become an activist,” he says. “I’m trying to save my life.”